Second Generation BTK Inhibitors: Reviewing Data on CLL Treatments

Adam Kittai, MD, hematologist and assistant professor of medicine, Ohio State University, shares how second generation BTK inhibitors are changing treatment decisions in chronic lymphocytic leukemia, and adds what payers should keep in mind as new data becomes available.

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Welcome back to PopHealth Perspectives, a conversation with the Population Health Learning Network where we combine expert commentary and exclusive insight into key issues in population health management and more.

In this episode, Dr Adam Kittai reviews how second generation BTK inhibitors are transforming care for patients with CLL.

Hi, my name is Adam Kittai and I'm an assistant professor at the Ohio State University. I did my fellowship training focused on clinical and basic research in lymphoma and leukemia at Oregon Health and Science University. I've been at Ohio State University for 3 years now.

My research is in CLL and related disorders. I'm a clinical investigator focused on bringing cellular therapies to high risk and relapse-refractory CLL. I also have a specific interest in Richter's transformation, which is when CLL transforms to an aggressive lymphoma.

Thank you, Dr Kittai. Can you discuss how the introduction of second generation BTK inhibitors has changed the treatment landscape for your patients with CLL?

Sure. The Bruton's tyrosine kinase inhibitor ibrutinib revolutionized the treatment of CLL, with multiple studies showing its superiority to chemoimmunotherapy. Furthermore, since ibrutinib is a pill that patients take once a day, patients were able to live their full lives without having to come to the hospital or clinic for infusions.

Over time, though, investigators noted concerning toxicities with ibrutinib, specifically regarding atrial fibrillation, cardiac arrhythmias, hypertension, and bleeding. Although these toxicities can be managed and some occur in less than 10% of individuals, anything cardiac-related is taken very seriously in our books.

This led to the development of the second generation BTK inhibitors, acalabrutinib and zanubrutinib. Both are considered cleaner. What does that mean?

When we develop targeted therapy—in this case, drugs that target BTK—they are considered clean if they only inhibit the specific kinase intended. Ibrutinib has a lot of off target effects, which has been beneficial in some ways, but has some negative consequences such as these increases in adverse events.

Acalabrutinib and zanubrutinib have fewer off target effects and are expected to cause less side effects. Compared to prior ibrutinib trials, less toxicity was observed in the phase 1 and 2 trials of acalabrutinib as monotherapy, and the phase 3 trial of acalabrutinib vs chemoimmunotherapy called ELEVATE TN. This led to many providers starting to choose acalabrutinib instead of ibrutinib once it was FDA approved.

Furthermore, since the second generation BTK inhibitors target the same kinase, it was expected that they would have equal efficacy to ibrutinib. But the true test to determine if one drug has less toxicity or works better than another is comparing the drugs directly to each other in a randomized trial. This led to the development of the ELEVATE RR and ALPINE studies. ELEVATE RR compared acalabrutinib to ibrutinib, and ALPINE compared zanubrutinib to ibrutinib. Both trials were in the relapse-refractory setting, so not the treatment-naive setting.

ELEVATE RR has been published in the Journal of Clinical Oncology. It accrued patients with high-risk disease having either deletion 17p or deletion 11q. It met its primary endpoint, which was noninferiority of progression-free survival (PFS) of ibrutinib compared to acalabrutinib, meaning they had equal efficacy in this setting. It also met one of its secondary endpoints, which was less all-grade atrial fibrillation. I will note that grade 3 atrial fibrillation was equal in both arms.

Other adverse events that were improved with acalabrutinib were hypertension, joint pain, and bruising. Likely, we need more follow up, as hypertension became more apparent with ibrutinib as follow up continued. Of note, acalabrutinib is associated with headaches, which was also observed in this trial.

ALPINE, on the other hand, has not been fully published so we don't have all the data available just yet. ALPINE was designed a little differently than ELEVATE RR in that all relapse-refractory patients were included in this study—it did not just accrue high-risk patients like ELEVATE RR did. It was also a superiority trial, meaning researchers were aiming to show an improvement in efficacy with zanubrutinib over ibrutinib, as opposed to equal efficacy.

The primary endpoint in the ALPINE study was also different, as it was investigator-determined overall response rate. This has been a point of contention amongst investigators, as overall response rate is not seen as the most important endpoint in CLL since many patients on a BTK inhibitor can maintain a partial response for years. What is more important in our eyes are PFS, overall survival, and times to next treatment.

Also, it appears that they didn't include partial response with lymphocytosis in their overall response assessments, which is a little strange. We consider partial response with lymphocytosis as part of the group of patients that do attain an overall response. The endpoint of overall response is not one that we hold to the highest regard in this particular trial.

They do have a secondary endpoint of PFS, which will be something we look forward to seeing in the future, as well as independent review committee-assessed overall response rate. In 2021, it was first shown that zanubrutinib was superior to ibrutinib in investigator-assessed overall response at an interim analysis. Recently, this improvement in overall response rate was confirmed in independent review at the final analysis. Per the announcement, I'm not sure if partial response with lymphocytosis was included in the independent review analysis.

They also observed improvement in rates of atrial fibrillation and a lower rate of treatment discontinuation in patients who received zanubrutinib. There are certainly signs that zanubrutinib is associated with higher rates of neutropenia, but it is unclear if this leads to higher rates of infection, as this was not apparent in the initial presentation of the study. Overall, ALPINE looks like it may show improvement of overall response rate and PFS as well as atrial fibrillation with zanubrutinib over ibrutinib, but longer follow up is needed.

It's hard to make any concrete statements about zanubrutinib vs acalabrutinib because the trials were so differently designed. I don't expect a head-to-head trial of these two drugs any time soon.

Overall, I would say that second generation BTK inhibitors are very promising. Many people are using them instead of ibrutinib given their improved safety profile. There are signs that zanubrutinib may have improved efficacy over ibrutinib, but further follow up is definitely needed.

As new data becomes available, what should payers keep in mind when determining coverage options for this patient population?

I think the key is safety. I think more and more clinicians are going to prescribe acalabrutinib and zanubrutinib since the safety profile looks improved and efficacy is the same, if not better than ibrutinib. This is especially true for zanubrutinib.

Since acalabrutinib and zanubrutinib are safer than ibrutinib, they should be covered. These drugs will possibly lead to improved long term health over time, as atrial fibrillation can result in high morbidity. Soon, zanubrutinib will likely be approved in the frontline setting based on the SEQUOIA trial as well.

The bigger question that will arise is whether the second generation BTK inhibitors can be switched with ibrutinib when considering combination therapy. I think soon we will see approval of ibrutinib plus venetoclax in the treatment-naïve setting after the GLOW trial results, and clinicians are going to want to use second generation inhibitors here in combination with venetoclax as opposed to ibrutinib. In my opinion, if there's a safety reason for using the second generation inhibitors here, it should be allowed and considered. There is combination data available showing the safety of second generation inhibitors with venetoclax, justifying their use in the frontline setting.

Is there anything else that you feel we missed that you wanted to add today?

It's an exciting time in CLL and I really look forward to the final results of ALPINE and randomized trials that are looking at combination BTKi and BCL2.

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This transcript has been edited for clarity.